It is highly important and challenging to develop donor-acceptor-donor structured small-molecule second near-infrared window (NIR-II) dyes with excellent properties such as water-solubility and chem/photostability. Here, we discovery an electron acceptor, 6,7-di(thiophen-2-yl)-[1,2,5]thiadiazolo[3,4-g]quinoxaline (TQT) with highest stability in alkaline conditions, compared with conventional NIR-II building block benzobisthiadiazole (BBT) and 6,7-diphenyl-[1,2,5] thiadiazolo[3,4-g]quinoxaline (PTQ). The sulfonated hydrophilic dye, FT-TQT, is further synthesized with 2.13-fold increased quantum yield than its counterpart FT-BBT with BBT as acceptor. FT-TQT complexed with FBS is also prepared and displays a 16-fold increase in fluorescence intensity compared to FT-TQT alone. It demonstrates real-time cerebral and tumor vessel imaging capability with µm-scale resolution. Dynamic monitoring of tumor vascular disruption after drug treatment is achieved by NIR-II fluorescent imaging. Overall, TQT is an efficient electron acceptor for designing innovative NIR-II dyes. The acceptor engineering strategy provides a promising approach to design next generation of NIR-II fluorophores which open new biomedical applications.

compared with small molecular drugs. However, Food and Drug Administration (FDA) approval of nanosized agents has been hindered by their often complex and ambiguous chemical formulas. [2] Small molecular self-assembled nanoparticles have the potential to combine the small molecular compounds' simple chemical formulas advantage with the traditional nanoparticles' promising tumor accumulation advantage, which would make the FDA approval easier. However, small-molecule-based nanoprobes with desirable tumor microenvironment response abilities and outstanding in vivo performance are scanty. Although many existing small molecules have "smart" properties that allow them to respond to stimuli such as pH changes, small molecules that are sensitive in narrow physiological pH ranges (≈6.8-7.4) have been difficult to design. Typically, acidic microenvironments are found in solid tumor tissues (pH 6.5-6.8), [1] inflammatory sites, [3] and are associated with bone resorption by osteoclasts (pH < 5.5). [4] A pH-sensitive agent that can respond to the acidic microenvironment of solid tumor tissues (pH 6.5-6.8) [1] would be invaluable for potential theranostics of diseases. Previous sharp pH responsive polymer based nanoparticles (translation at pH 6.7, ΔpH ON/OFF < 0.25) could Development of novel nanomaterials for disease theranostics represents an important direction in chemistry and precision medicine. Fluorescent molecular probes in the second near-infrared window (NIR-II, 1000-1700 nm) show high promise because of their exceptional high detection sensitivity, resolution, and deep imaging depth. Here, a sharp pH-sensitive self-assembling cyclopeptide-dye, SIMM1000, as a smart nanoprobe for NIR-II imaging of diseases in living animals, is reported. This small molecule assembled nanoprobe exhibits smart properties by responding to a sharp decrease of pH in the tumor microenvironment (pH 7.0 to 6.8), aggregating from small nanoprobe (80 nm at pH 7.0) into large nanoparticles (>500 nm at pH 6.8) with ≈20-30 times enhanced fluorescence compared with the non-self-assembled CH-4T. It yields micrometer-scale resolution in blood vessel imaging and high contrast and resolution in bone and tumor imaging in mice. Because of its self-aggregation in acidic tumor microenvironments in situ, SIMM1000 exhibits high tumor accumulation and extremely long tumor retention (>19 days), while being excretable from normal tissues and safe. This smart self-assembling small molecule strategy can shift the paradigm of designing new nanomaterials for molecular imaging and drug development.Development of nanomaterials for molecular imaging and treatment of disease is a highly promising and dynamic field in chemistry and precision medicine. Nanomaterials offer numerous benefits for cancer theranostics development, such as long-circulation time, excellent tumor microenvironment response abilities, and the enhanced permeability and retentionThe ORCID identification number(s) for the author(s) of this article can be found under

Colorectal cancer (CRC) ranks as the third common and the fourth lethal cancer type worldwide. Immune checkpoint blockade therapy demonstrates great efficacy in a subset of metastatic CRC patients, but precise activation of the antitumor immune response at the tumor site is still challenging. Here a versatile prodrug nanoparticle for second near‐infrared (NIR‐II) fluorescence imaging‐guided combinatory immunotherapy of CRC is reported. The prodrug nanoparticles are constructed with a polymeric oxaliplatin prodrug (PBOXA) and a donor–spacer–acceptor–spacer–donor type small molecular fluorophore TQTCD. The later displays large Stokes shift (>300 nm), fluorescence emission over 1000 nm, and excellent photothermal conversion performance for NIR‐II fluorescence imaging‐guided photothermal therapy (PTT). The prodrug nanoparticles show seven times higher intratumoral OXA accumulation than free oxaliplatin. TQTCD‐based PTT and PBOXA‐induced chemotherapy trigger immunogenic cell death of the tumor cells and elicit antitumor immune response in a spatiotemporally controllable manner. Further combination of the prodrug nanoparticle‐based PTT/chemotherapy with programmed death ligand 1 blockade significantly promotes intratumoral infiltration of the cytotoxic T lymphocytes and eradicates the CRC tumors. The NIR‐II fluorescence imaging‐guided immunotherapy may provide a promising approach for CRC treatment.

Early and accurate assessment of therapeutic response to anticancer therapy plays an important role in determining treatment planning and patient management in clinic. Magnetic rseonance imaging (MRI) of necrosis that occurs after cancer therapies provides chances for that. Here, we reported three novel MRI contrast agents, GdL 1 , GdL 2 , and GdL 3 , by conjugating rhein with gadolinium 2-[4,7,10-tris(carboxymethyl)-1,4,7,10tetraazacyclododec-1-yl]acetic acid (Gd-DOTA) through different linkers. The T1 relaxivities of three probes (7.28, 7.35, and 8.03 mM −1 s −1 ) were found to be higher than that of Gd-DOTA (4.28 mM −1 s −1 ). Necrosis avidity of GdL 1 was evaluated on the rat models of reperfused liver infarction (RLI) by MRI, which showed an increase of T1-weighted contrast between necrotic and normal liver during 0.5−12 h. Besides, L 1 was also labeled with 64 Cu to assess its necrosis avidity on rat models of RLI and muscle necrosis (MN) by a γ-counter. The uptakes of 64 CuL 1 in necrotic liver and muscle were higher than those in normal liver and muscle (P < 0.05). Then, the ability of GdL 1 to assess therapeutic response was tested on rats bearing Walker 256 breast carcinoma injected with a vascular disrupting agent CA4P by MR imaging. The signal intensity of tumoral necrosis was strongly enhanced, and the contrast ratio between necrotic and viable tumor was 1.63 ± 0.11 at 3 h after administration of GdL 1 . Besides, exposed DNA in necrosis cells may be an important mechanism of three probes targeting to necrosis cells. In summary, GdL 1 may serve as a promising MRI contrast agent for accurate assessment of treatment response.

ABSTRACT:Rapid detection and precise evaluation of myocardial viability is necessary to aid in clinical decision making whether to recommend revascularization for patients with myocardial infarction (MI). Three novel 18 F-labeled 1-hydroxyanthraquinone derivatives were synthesized, characterized, and evaluated as potential necrosis avid imaging agents for assessment of myocardial viability. Among these tracers, [ 18 F]FA3OP emerged as the most promising compound with best stability and highest targetability. Clear PET images of [ 18 F]FA3OP were obtained in rat model of myocardial infarction and reperfusion at 1 h after injection. In addition, the possible mechanisms of [ 18 F]FA3OP for necrotic myocardium were discussed. The results showed [ 19 F]FA3OP may bind DNA to achieve targetability to necrotic myocardium by intercalation. In summary, [ 18 F]FA3OP was a more promising "hot spot imaging" tracer for rapid visualization of necrotic myocardium.

Azide is an important chemical functional group and has been widely used in chemical biology. However, the impact of azide on the in vivo behaviors of compounds has been rarely studied. Herein, azide was introduced into a fluorescent dye for the near-infrared window two (NIR-II) bone imaging. Specifically, we designed and synthesized the small-molecule NIR-II dyes, N 3 -FEP-4T capped with azide and FEP-4T without azide capping. In vitro assays revealed that N 3 -FEP-4T showed 5and 5.6-times higher hydroxyapatite accumulation and macrophage uptake than those of FEP-4T, respectively. Moreover, N 3 -FEP-4T displayed higher bone uptakes and much better bone NIR-II imaging quality, demonstrating the specific bone-targeting ability of the azide-containing probe. N 3 -FEP-4T was then further successfully used for osteoporosis NIR-II imaging. Overall, our study provides insights into the impact of azide on the in vivo behavior of azide-containing compounds and opens a new window for biological application of azide.

Near-infrared window IIb (NIR-IIb, 1500–1700 nm) fluorescence imaging demonstrates attractive properties including low scattering, low absorption, and deep tissue penetration, and photothermal therapy (PTT) is also a promising modality for cancer treatment. However, until now, there is no report on theranostic systems based on small organic molecules combining fluorescence imaging in the NIR-IIb and PTT, highlighting the challenge and strong need for development of such agents. Herein, we report a novel small molecule NIR-IIb dye IT-TQF with a D–A–D structure, which exhibited high fluorescence intensity in the NIR-IIb window. To further translate IT-TQF into an effective theranostic agent, IT-TQF was encapsulated into DSPE-PEG2000 to construct IT-TQF NPs. The physical and photochemical properties of the nanoprobe were investigated in vitro, and the in vivo NIR-IIb imaging and PTT performance were evaluated in normal, subcutaneous, orthotopic, and metastatic tumor mice models. IT-TQF NP-based NIR-IIb imaging demonstrated high spatial resolution and high tissue penetration depth, and small normal blood vessels (55.3 μm) were successfully imaged in the NIR-IIb window. Subcutaneous, orthotopic, and metastatic tumors were all clearly delineated. A high tumor signal-to-background ratio (SBR) of 9.42 was achieved for orthotopic osteosarcoma models, and the erosions of bone tissue caused by tumor cells were precisely visualized. Moreover, NIR-II image-guided surgery was successfully performed to completely remove the orthotopic tumor. Importantly, IT-TQF NPs displayed high PTT efficacy (photothermal conversion efficiency: 47%) for effective treatment of tumor mice. In conclusion, IT-TQF NPs are a novel and promising phototheranostic agent in the NIR-IIb window, and the nanoprobe has high potential for a broad range of biomedical applications.

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